Translation of dipeptide repeat proteins in C9ORF72 ALS/FTD through unique and redundant AUG initiation codons

  1. Yoshifumi Sonobe
  2. Soojin Lee
  3. Gopinath Krishnan
  4. Yuanzheng Gu
  5. Deborah Y Kwon
  6. Fen-Biao Gao
  7. Raymond P Roos  Is a corresponding author
  8. Paschalis Kratsios  Is a corresponding author
  1. University of Chicago, United States
  2. University of Massachusetts Medical School, United States
  3. Biogen, United States

Abstract

A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A hallmark of ALS/FTD pathology is the presence of dipeptide repeat (DPR) proteins, produced from both sense GGGGCC (poly-GA, poly-GP, poly-GR) and antisense CCCCGG (poly-PR, poly-PG, poly-PA) transcripts. Translation of sense DPRs, such as poly-GA and poly-GR, depends on non-canonical (non-AUG) initiation codons. Here, we provide evidence for canonical AUG-dependent translation of two antisense DPRs, poly-PR and poly-PG. A single AUG is required for synthesis of poly-PR, one of the most toxic DPRs. Unexpectedly, we found redundancy between three AUG codons necessary for poly-PG translation. Further, the eukaryotic translation initiation factor 2D (EIF2D), which was previously implicated in sense DPR synthesis, is not required for AUG-dependent poly-PR or poly-PG translation, suggesting that distinct translation initiation factors control DPR synthesis from sense and antisense transcripts. Our findings on DPR synthesis from the C9ORF72 locus may be broadly applicable to many other nucleotide-repeat expansion disorders.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Yoshifumi Sonobe

    University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  2. Soojin Lee

    RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.
  3. Gopinath Krishnan

    RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.
  4. Yuanzheng Gu

    Neuromuscular and Movement Disorders, Biogen, Cambridge, United States
    Competing interests
    Yuanzheng Gu, is affiliated with Biogen. The author has no financial interests to declare..
  5. Deborah Y Kwon

    Neuromuscular and Movement Disorders, Biogen, Cambridge, United States
    Competing interests
    Deborah Y Kwon, is affiliated with Biogen. The author has no financial interests to declare..
  6. Fen-Biao Gao

    RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.
  7. Raymond P Roos

    University of Chicago, Chicago, United States
    For correspondence
    rroos@neurology.bsd.uchicago.edu
    Competing interests
    No competing interests declared.
  8. Paschalis Kratsios

    University of Chicago, Chicago, United States
    For correspondence
    pkratsios@uchicago.edu
    Competing interests
    Paschalis Kratsios, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1363-9271

Funding

Association for Frontotemporal Degeneration

  • Paschalis Kratsios

National Institute of Neurological Disorders and Stroke (R37NS057553)

  • Fen-Biao Gao

National Institute of Neurological Disorders and Stroke (R01NS101986)

  • Fen-Biao Gao

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2023, Sonobe et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yoshifumi Sonobe
  2. Soojin Lee
  3. Gopinath Krishnan
  4. Yuanzheng Gu
  5. Deborah Y Kwon
  6. Fen-Biao Gao
  7. Raymond P Roos
  8. Paschalis Kratsios
(2023)
Translation of dipeptide repeat proteins in C9ORF72 ALS/FTD through unique and redundant AUG initiation codons
eLife 12:e83189.
https://doi.org/10.7554/eLife.83189

Share this article

https://doi.org/10.7554/eLife.83189

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